Title: On the relationship among QT interval, atrial fibrillation, and torsade de pointes
Abstract: The uncommon congenital syndromes of QT prolongation associated with a high risk of sudden death (SD) were first described in the 1950s and 1960s,1–3 and the term torsade de pointes (TdP) was coined in the mid-1960s to describe the peculiar polymorphic ventricular tachycardia that can arise at slow heart rates when the QT is very long.4 The notion that drugs could produce a very similar clinical syndrome, with striking QT prolongation and polymorphic tachycardia, was first noted in the same era,5,6 and became increasingly well recognized with antiarrhythmic therapies during the 1970s and 1980s. The idea that ‘non-cardiovascular’ drugs could prolong the QT interval, and trigger TdP (or even SD), remained an arrhythmia curiosity until the initial report of terfenadine-associated TdP in the late 1980s.7 Review of the extant safety data, and a series of clinical and in vitro mechanistic studies, identified inhibition of CYP3A4-mediated terfenadine biotransformation to an antihistamine metabolite (fexofenadine) as the major mechanism.8–10 Terfenadine itself turned out to be a very potent QT prolonging agent, and that is now well recognized as a reflection of its ability to block the rapid component of the cardiac delayed rectifier I Kr. Indeed, block of I Kr, or in occasional instances reduction of the current by other mechanisms,11,12 is the major mechanism underlying virtually all forms of drug-induced TdP.13
The reason the terfenadine incident proved so important for drug development was not only the elucidation of underlying mechanisms, but also the recognition that even a small risk of a very serious side effect, such as drug-induced TdP, could upset the balance between risk and benefit that goes into the prescription of any drug. In the case of terfenadine, regulatory agencies viewed the benefit …